Objective: A major barrier to the advancement of diagnostic and therapeutic nanomedicines has been the non-target retention caused by the accumulation of the drug delivery systems in organs associated with the mononuclear phagocyte system, particularly the liver and spleen. The focus of this proposal is on the development of 177Lu-DOTA-Metabolically Active Linkers (MALs) that substantially reduce the non-target retention of diagnostic and radiotherapeutic HPMA copolymers, thereby leading to an increase in the tumor to- non-target ratios. We propose to design and develop MALs that enzymatically cleave in the presence of Cathepsins B and S, which are known to be highly expressed in the liver and spleen. Cleavage of the MALs will generate low molecular weight radiometabolites which are expected to clear more effectively from nontarget tissue while still achieving significant retention in tumors. For therapeutic applications, this enhanced clearance from non-target tissues will substantially decrease non-target toxicity. If successful, the MAL stratagem will be easily integrated into a wide variety of nanomedicine platforms to substantially enhance the efficacy and translational potential of these agents for treating cancer and other diseases. Study Design: The first aim of this proposal is to synthesize, purify, characterize and radiolabel the 177Lu- DOTA-MAL-HPMA copolymers. Upon synthesizing the agents, the intemalization, efflux and metabolism properties of the agents will be investigated in human macrophage and the HPAC pancreatic cancer cell line. The second aim of the proposal will focus on the initial in vivo evaluation of the 177Lu-DOTA-MAL-HPMA copolymers. These studies will include biodistribution, human dose estimation, in vivo metabolism and microSPECT/CT imaging studies. Lastly, the third aim will evaluate the therapeutic potential of the 177Lu- DOTA-MAL-HPMA copolymers alone and in combination with current pancreatic cancer chemotherapeutic regimens. As part of the therapeutic evaluation, maximum tolerated dose determinations and histopathological analysis will be performed to gauge therapeutic efficacy and toxicity.